In the administration of drugs and in the diagnosis of certain pathological conditions it is highly desirable, if not necessary, to effect a controlled release of one or more substances within the living organism, in particular within a mammalian host. For example, the controlled release of drugs (a term used hereinafter to include all substances which effect some biological response) over a period of time within a specified region or organ of the body can be used as a continuous dose, long-term delivery system for such agents as antibiotics, cardioactive medicaments, narcotic antagonists, hypoglycemic agents, fertility control agents, and the like. Likewise, the implantation of a diagnostic substance such as a dye can be used to monitor the presence or absence of a pathological condition. Devices for administering such a controlled release of drugs are generally referred to as "depots or implants", the latter term being used throughout the following description and claims.
1. Field of the Invention
Continuous, long term drug delivery devices have distinct advantages over oral administration or direct injection of drugs since neither of these earlier developed modes can achieve a desired blood level of a drug in circulation for an extended period of time. Oral administration or direct injection bring about a pulse entry of the drug which may create drug concentrations beyond the capacity of the active centers to accept the drug, and may also exceed the capacity of the metabolic and excretory mechanism of the living organism. Thus, if the level of the drug remains elevated, tissues and/or organs may sustain detrimental effects. One technique for reducing excessive concentrations has been to modify the drug structure to provide a longer metabolic half-life; but this in turn has frequently demonstrated lowered therapeutic effectiveness.
To avoid the disadvantages of oral or direct injection administration of drugs, a number of modes of administration of continuous dose, long-term delivery devices have been used or proposed. These include devices based upon ingestion, injection, vaginal and uterine insertion, percutaneous application (see for example, U.S. Pat. Nos. 3,598,122 and 3,598,123) and subcutaneous implantation. While all of these routes of administration may be found useful under one set of circumstances or the other, the use of subcutaneous implants offers a particularly desirable combination of properties to permit the administration of substances on a localized or systemic basis. To this end, subcutaneous implants serving as depots capable of slow release of a drug have been proposed. These implants suggest the possibility of attaining continuous administration over a prolonged period of time to achieve a relatively uniform delivery rate and, if desired, a static blood level. Since an excessive concentration of drug never enters the body fluids, problems of pulse entry are overcome and metabolic half-life is not a factor of controlling importance.
Despite the advantages of administering drugs from implants, prior art devices designed for this purpose have possessed one or more disadvantages which limit their acceptability and efficacy. Among such disadvantages are nonbiodegradability which may require a surgical procedure to remove them; nonbiocompatibility which may result in the introduction of undesirable and even harmful substances into the body; antigenicity which gives rise to the production of unwanted antigen bodies in the system; and difficulty in controlling release rates of the drugs.
2. Description of the Prior Art
In the prior art, a number of matrix materials and several different structural designs have been proposed for subcutaneous implants. Such materials as hydrogels, gelatin, carboxymethyl cellulose, organopolysiloxane rubbers, polyurethanes, waxes, polyvinyl alcohol, polyglycolic acid, and polylactic acid have been suggested for this purpose.
Those matrix materials, such as carboxymethyl cellulose and polyvinyl alcohol, which are water-soluble are unsatisfactory because it is not possible to control the drug release rate from them over any appreciable length of time. Those matrix materials, such as hydrogels, gelatin and collagens, which are water-swellable provide inherently rapid drug release because of their inability to retain the drug in a swelled condition. Moreover, a material such as gelatin has an extremely complex chemical structure formed of some twenty amino acids and there appears to be no satisfactory way to control or adjust its physical properties for use as an implant matrix. Collagen-based implants are described in the literature (see for example Rubin et al "Collagen as a Vehicle for Drug Delivery", The Journal of Clinical Pharmacology, August-September, 1973, pp. 309-312.)
More recently, absorable, biocompatible matrix materials formed of polyglycolic acids, polylactic acids or mixtures of these have been disclosed. (See for example U.S. Pat. No. 3,773,919 and reports on Contract DADA-17-72-C-2079 to Dynatech Research and Development Co., with U.S. Army Medical Research and Development Command, Washington D.C. (1972).) These delivery devices consist of a polymer matrix in which the drug is physically entrapped. The drug is released, not by diffusing through a polymeric membrane, but by hydrolytic breakdown of the polymer matrix itself. As the polymeric matrix disintegrates, the enclosed drug is released into the surrounding body fluids. By the time all of the drug has been released from the matrix, the polymer fragments have been almost completely absorbed. Although these matrix materials make it possible to provide biodegradable and biocompatible implant devices having less rapid release rates, they present serious problems in the accurate control of release rates. These problems in release rate control arise because the polylactic acids and polyglycolic acids in degradation break down to form lactic acid and glycolic acid. Degradation is the result of hydrolysis which is dependent upon both pH and degree of crystallinity of the polymers. Since the products of these hydrolysis reactions are acids, there is a tendency for the products that do not immediately diffuse away from the implant site to accelerate further hydrolysis. In addition, the crystalline regions degrade at a much slower rate than the amorphorus regions, thus giving rise to a nonuniform degradation pattern and a porous structure from which the drugs may be released at an uncontrollable rate.
Organopolysiloxane rubbers as carriers for the controlled release of drugs have received widespread attention. The use of such materials in implant devices is described in U.S. Pat. Nos. 3,279,996 and 3,518,340. Implants which use any of these materials as substrates or carriers which are not absorbable by the living organism into which they are introduced normally require removal by surgery. The silicone rubbers are among the nonabsorbable materials and therefore they suffer from this drawback. Typically, implants formed of silicone rubber, or of any of the other above-named materials, have been fabricated either in the form of closed hollow tubes or capsules (with or without a sponge sleeve) in which the drug is contained for diffusion through the tube walls; or they have been made up into structures of homogeneous polymer-drug blends. Another type of subcutaneous implant which requires removal is described in U.S. Pat. No. 2,625,158.
Some work has been reported on implants formed by chemically bonding drugs to polypeptides (see for example Jablon, P. A. M., Ph.D. Thesis, Purdue University, 1969). This approach necessitates providing a drug having a reactive site amenable to chemical bonding to the polypeptide; and it also introduces the danger that in the breaking of the chemical bond to release the drug the effectiveness and acceptability of the drug to the system may be materially altered. Moreover, the drug-polypeptide complex will, in fact, represent a new drug of unknown properties. Finally, an implant in which the drug is chemically bonded to the matrix material can not release the drug from the matrix by the process of diffusion, since release is predicated on the actual breaking of chemical bonds.
U.S. Pat. No. 3,493,652 teaches the incorporation of medicaments such as cardioactive, adrenergic, cholinergic, antispasmodic and curariform agents, tranquilizers, antihistamines, antibiotics and the like into a matrix which contains one or more enzymes or enzyme precursors capable of digesting the matrix material which, in turn, may be formed of such diverse materials as casein, fibrinogen, proteins, polypeptides with free amino groups, urea and amino acids. The dosage formulation may take many different forms including suspensions, emulsions, tablets (sublingical, buccal, oral or vaginal), capsules, ointments, suppositories and implants. When such a controlled release medicament is introduced into a living organism it must, of necessity, introduce both the substrate material and enzyme into the system and one or both of these may be antagonistic to the system. In particular, to introduce those enzymes which are not normally present in the living organism may result in harmful side effects. Moreover, enzymes are known to degrade or denature and this process may take place prior or subsequent to the administration of the dosage. In the first case, the effectiveness of the dosage-contained enzyme is lessened or even cancelled; and in the second case, premature enzyme degradation could materially alter or even destroy any control over the drug release rate.
A field which is somewhat related to implants is that concerned with sutures. Prior art in this field teaches, among many variations, the incorporation of antiseptics into sutures derived from animal tissue (U.S. Pat. Nos. 923,768 and 1,382,715); sutures of proteins or other nitrogenous amphoteric organic materials having a germacide chemically bonded thereto (U.S. Pat. No. 3,642,003); and sutures formed of or incorporating polymers and/or copolymers of glycolic acid and lactic acid (U.S. Pat. Nos. 3,636,956 and 3,736,646). Finally, the prior art discloses biodegradable sutures formed of a copolymer of glycolic and lactic acids (U.S. Pat. No. 3,736,646) and of a polylactide polymer or copolymer (U.S. Pat. No. 3,636,956).
Inasmuch as the matrix materials of the implant devices of this invention are polypeptides, i.e., poly-.alpha.-amino acids, the prior art disclosing the use of polypeptides in therapeutic devices also deserves attention. Such prior art includes sutures made of copolypeptides (U.S. Pat. No. 3,371,069); wound dressings formed of a polypeptide film containing a therapeutic agent and a carrier which transports the therapeutic agent to the dressing surface (U.S. Pat. No. 3,867,520) and dressings for burn wounds formed of a nylon velour fabric laminated with a synthetic polypeptide material designed to cover burns to provide a framework into which fibroblastic proliferation could occur (Spira et al "Evaluation of Synthetic Fabrics as Artificial Skin Grafts to Experimental Burn Wounds" J. Biomed, Mater. Res., 3: 213-234 (1969) and Walder et al "Evaluation of Synthetic Films as Wound Covers" Trans. Amer. Soc. Artif. Int. Organs, 15: 29-32 (1969).)
It will thus be apparent from this discussion of the prior art that implants for controlled drug release have distinct theoretical advantages; but that there is a need for an improved implant device to achieve a continuous dose, controlled release of drugs or other substances which overcome the major disadvantages (i.e., difficulty in continuously controlling the release of the drugs, production of unwanted degradation products and/or the need for surgically removing the implanted matrix) associated with the presently available implant devices.